Multiple studies have demonstrated that tumors are able to establish an immunosuppressive microenvironment to escape immune surveillance and promote tumor development. Regulatory T cells (Tregs) are an important component of the immunosuppressive milieu in the tumor environment and work by dampening T cell immunity to tumor associated antigens. Tregs are therefore a major obstacle in mounting an effective anti-tumor immune response. Depletion of Tregs in murine models of cancer inhibits tumor growth; however, the accompanying autoimmune and inflammatory disorders associated with a complete depletion of Tregs may limit the clinical utility of this approach. Strategies which specifically target Tregs, in the inflammatory tumor microenvironment, may be a viable alternative. Recent studies in several laboratories have identified Neuropilin 1 (NRP-1) as a candidate target for modulating Treg activity in tumors without impacting Tregs in the periphery (see, e.g., Chaudhary and Elkord, Vaccines (2016) September; 4(3): 28; Bos et al., J Exp Med (2013) 210 (11):2435-66; Teng et al., Cancer Res. (2010) 70 (20):7800-.
NRP-1 is a multifunctional 130-kDa transmembrane protein with a large extracellular domain containing two N-terminal CUB domains (a1 and a2), two coagulation factor V/VIII homology domains (b1 and b2) and a single MAM domain (c). The cytoplasmic tail is short and does not display any catalytic activity on its own. NRP-1 is a receptor with multiple known ligands and co-receptors, including semaphorins, VEGF, P1GF and plexins, among others (Appleton et al., Embo J. (2007) November 28; 26(23): 4902-4912).
NRP-1 is expressed on human and murine Tregs, and this expression identifies a highly-suppressive Treg subset. Within the tumor microenvironment, NRP-1 expression is required for Treg stability and function but does not impact Tregs outside the inflammatory environment of tumors. Recent studies have identified the immune cell-expressed ligand semaphorin 4A (Sema4a) as an additional ligand for NRP-1, and demonstrated that the sema4a/NRP-1 interaction is an important mediator of Treg stability in vitro and in inflammatory sites in vivo. These data suggest that NRP-1 is required for Treg lineage stability and function (see, e.g., Delgoffe et al., Nature (2013) September 12; 501(7466):252-6.).
Several lines of evidence support the utility of targeting the interaction of NRP-1 and its associated proteins, in particular targeting the NRP-1/Sema axis, on Tregs as a strategy for modulating the immunosuppressive microenvironment found in tumors. For instance, mice with Treg targeted NRP-1 knock-out exhibit reduced tumor growth in several murine tumor models, without any other autoimmune phenotypes. Additionally, antagonists to NRP-1 or Sema reverse Treg suppressive activity and demonstrate anti-tumor efficacy again in the absence of autoimmune adverse events. Furthermore, the NRP-1-VEGFA axis has been proposed as an important pathway regulating the chemotaxis of Tregs into the tumor micro-environment, and an antagonistic Ab that blocks this interaction on Tregs could inhibit the influx of these suppressive cells into the tumor.
There is emerging evidence suggesting the NRP-1 is expressed on the surface of immune cells in human tumors. NRP-1+Tregs are found in the draining lymph nodes (DLN) from cervical cancer patents, and there was a significant drop in the percentage of Tregs in DLN in patients with a pathological response to preoperative chemoradiation. In addition, NRP-1+Tregs have been observed in tumor infiltrating lymphocytes (TILs) in patients with melanoma and head and neck squamous cell carcinoma.
Thus, there is a need for therapeutics that can antagonize NRP-1 without inducing autoimmune disease. Provided herein are ABPs that fulfill this need.